Brinkhous K M, Sigman J L, Read M S, Stewart P F, McCarthy K P, Timony G A, Leppanen S D, Rup B J, Keith J C, Garzone P D, Schaub R G
Department of Pathology, University of North Carolina at Chapel Hill 27599-7525, USA.
Blood. 1996 Oct 1;88(7):2603-10.
Recombinant human factor IX (rFIX) has been expressed in transduced cultured cell systems since 1985. Because there has been limited in vivo testing of rFIX in hemophilia B subjects, this study was undertaken using the severe hemophilia B canines of the Chapel Hill strain. Three groups of hemophilic dogs received either 50, 100, or 200 IU/kg of rFIX. As a control, a fourth group of hemophilic dogs received 50 IU/kg of a high purity, plasma-derived human FIX (pdFIX). The coagulant and hemostatic effects of rFIX and pdFIX were similar with all comparative dosing regimens. Based on activity data, the elimination half-life of rFIX was 18.9 +/- 2.3 hours and pdFIX was 17.9 +/- 2.1 hours. A prophylactic regimen administering rFIX daily resulted in a continuous therapeutic level of plasma FIX and was accompanied by a two-fold increase in recovery levels by day 5, compared to that observed with administration of a single bolus. The mechanisms of the high to complete recovery of FIX with the prophylactic regimen could depend not only on the degree of saturation of the vascular endothelial binding sites but also on the altered dynamics of the balance of FIX distribution between the intravascular and extravascular compartments. The pharmacokinetic (PK) parameters for rFIX and pdFIX were similar. However, the relative PK values for V1 and V5s of both products on day 5 differed greatly from day 1 and may reflect the changing equilibrium of FIX between compartments with elevated levels of plasma FIX. Neutralizing antihuman FIX antibodies resulting from human FIX antigen being administered to FIX deficient dogs were observed beginning at 14 days. The antigenicity of rFIX and pdFIX appeared to be comparable. Despite the very different procedures used for production of rFIX and pdFIX products, in vivo testing in hemophilia B dogs showed the functional behavior of these products is similar; they are highly effective for replacement therapy and for prophylaxis.
自1985年以来，重组人凝血因子IX（rFIX）已在转导的培养细胞系统中表达。由于对B型血友病患者进行的rFIX体内测试有限，本研究使用了查珀尔希尔品系的重度B型血友病犬进行。三组血友病犬分别接受50、100或200 IU/kg的rFIX。作为对照，第四组血友病犬接受50 IU/kg的高纯度血浆源性人凝血因子IX（pdFIX）。在所有比较给药方案中，rFIX和pdFIX的凝血和止血效果相似。根据活性数据，rFIX的消除半衰期为18.9±2.3小时，pdFIX为17.9±2.1小时。与单次推注相比，每日给予rFIX的预防性方案可使血浆凝血因子IX维持持续治疗水平，并在第5天时恢复水平提高两倍。预防性方案使凝血因子IX高度至完全恢复的机制可能不仅取决于血管内皮结合位点的饱和程度，还取决于血管内和血管外间隙之间凝血因子IX分布平衡的动态变化。rFIX和pdFIX的药代动力学（PK）参数相似。然而，两种产品在第5天的V1和V5s相对PK值与第1天有很大差异，这可能反映了血浆凝血因子IX水平升高时隔室之间凝血因子IX平衡的变化。从第14天开始，观察到向凝血因子IX缺乏犬施用人类凝血因子IX抗原后产生的中和抗人凝血因子IX抗体。rFIX和pdFIX的抗原性似乎相当。尽管用于生产rFIX和pdFIX产品的程序非常不同，但在B型血友病犬中的体内测试表明，这些产品的功能行为相似；它们对替代疗法和预防非常有效。
